Targeting CDK in triple-negative breast cancer

A team at the University of California, San Francisco has
found a dysregulated MYC
pathway that underlies the majority of triple-negative breast cancers-a form of
the disease with limited treatment options.1 The researchers also
showed that inhibitors of cyclin
dependent
kinase, a target upon which MYC-upregulated cancers are
dependent, could selectively kill the triple-negative cancer cells.

The
group is planning a clinical trial of an undisclosed cyclin dependent kinase (CDK) inhibitor.

Due
to the lack of well-defined targets, developing targeted therapies against
triple-negative disease has been challenging. There are no approved targeted
therapies for triple-negative breast cancer, and standard care remains
chemotherapy.

Andrei
Goga, an associate professor of medicine at UCSF, has been tackling the
indication by looking for targets in oncogenic pathways outside of the hormone
receptors and HER2.

In
2007, Goga and colleagues reported that several other types of cancer with high
expression of MYC (c-Myc) become dependent on survivin (BIRC5), an inhibitor of apoptosis that is
rapidly degraded in the absence of CDK1 (CDC2) activity.2 The team also
showed that small molecule CDK1 inhibitors could exploit this vulnerability to
selectively kill survivin-dependent cancer cell lines.3

The
following year, a different group reported that about 70% of triple-negative
breast tumors are classified as basal-like, which often has an aggressive
phenotype.4

The
final puzzle piece came from multiple other groups that showed MYC plays an
important role in aggressive breast cancers, although those groups did not look
specifically at triple-negative breast cancers.5

Thus,
Goga's group sought to determine whether the MYC pathway was at work in
triple-negative breast cancer, and if so whether such tumors would be sensitive
to CDK inhibitors.

In
primary breast tumor samples, triple-negative samples showed significantly
higher expression of MYC mRNA and protein than receptor-positive samples (p<0.0001 and p<0.04). In a panel of
50 human breast cancer cell lines, MYC mRNA expression in the 25
triple-negative lines was greater than that in the non-triple-negative lines (p<0.01).

Moreover,
patients who had more MYC activity had significantly lower disease-free
survival and had early disease recurrence (p=0.005 and p=0.001).

With
the link established between triple-negative breast cancer, increased MYC
activity and poor disease prognosis, the researchers next sought to determine
whether their earlier findings with CDK inhibitors in other MYC-upregulated
cancers applied to this disease subgroup.

Purvalanol
A is a research reagent. Dinaciclib from Merck & Co. Inc. and Ligand Pharmaceuticals Inc. is in Phase II
testing to treat multiple hematological cancers and non-small cell lung cancer
(NSCLC). The compound is not being tested in breast cancer.

Results
were published in The Journal of Experimental Medicine. Merck declined to
comment, and Ligand did not respond to requests for an interview.

"The publication adds to previous data highlighting
a possible synthetic lethal relationship between the MYC oncoprotein and cyclin
dependent kinase enzymes in a variety of tumor types," said Sheelagh Frame,
seliciclib
program manager at Cyclacel Pharmaceuticals Inc.
"However, their analysis and interpretation is somewhat limited to the
basal subtype of triple-negative breast cancer, where it has previously been
reported that the MYC pathway signature shows a strong correlation with
basal-like histology. Future work would need to address whether MYC is
disproportionately upregulated in the other subtypes of triple-negative breast
cancer."

Cyclacel's
first-generation small molecule CDK inhibitor seliciclib is in Phase II testing
for nasopharyngeal cancer and NSCLC. The company's second-generation inhibitor,
CYC065, is in preclinical development for
cancer.

As multiple companies already are testing CDK
inhibitors in the clinic to treat other types of cancer, Goga said the clear
next step is to run a clinical study in triple-negative breast cancer. His
group is planning a trial, but further details were not disclosed.

He
did say it will be important to determine whether having a companion molecular
diagnostic for assessing MYC abundance would be useful in such a trial.

Goga
also noted that CDK inhibitors might have a synergistic effect with inhibitors
of poly(ADP-ribose) polymerase (PARP), one of the few targets companies
are pursuing for triple-negative breast cancer.

PARP
inhibitors could use the boost because despite their initial promise, this
class of compounds has encountered a string of setbacks in the clinic that have
led some to question the target's relevance in triple-negative tumors.

In
2011, Sanofi's PARP inhibitor iniparib failed in a Phase
III trial, and a study later that year from researchers at Abbott Laboratories suggested that iniparib's
primary mechanism of action is not PARP inhibition.7

In 2010, AstraZeneca plc closed
recruitment of patients with triple-negative breast cancer in a Phase I/II
trial of its PARP inhibitor olaparib after noting that this
particular cohort did not meet continuation criteria.

Although
Abbott's PARP inhibitor veliparib still is being
tested in patients who have triple-negative breast cancer, data from a Phase II
trial in 2009 suggested the compound's effect would be limited to the small
percentage of patients who also carry a mutation in the breast cancer 1 early onset
(BRCA1) or BRCA2 gene.8,9

Goga
noted that CDK inhibitors have the potential to expand the utility of PARP
inhibitors beyond patients with mutated BRCA, as a group at Dana-Farber Cancer Institute reported last year
that Cdk1 inhibition sensitized mice with wild-type Brca tumors to PARP
inhibitors.10

If
the Dana-Farber findings translate to the triple-negative breast cancer
setting, the results would suggest that CDK inhibitors could expand the use of PARP
inhibitors to the greater population of triple-negative patients who also
express wild-type BRCA.

Cyclacel's
Frame added that the researchers should carry out studies to determine the
relationship between different levels of MYC expression and sensitivity to CDK
inhibition. Moreover, she also wanted to know whether there is an association
between the levels of MYC and cyclin
E
(CCNE) expression in the primary patient
samples.

"Previous
reports have indicated that overexpression of cyclin E
is frequently found in triple-negative tumors and may confer hypersensitivity
to small molecule inhibitors of CDK2, such as seliciclib," she told SciBX.

On
the preclinical side, Goga's group is investigating the effects of CDK
inhibitors in primary triple-negative breast cancer xenograft mouse models and
trying to elucidate the mechanism behind BIM upregulation in response to CDK
inhibition.

Access this BioCentury Innovations article Cover Story for your individual use via a permanent link that allows you to read or print the article, and any sub-articles, charts, tables and/or graphs related to this specific story: $50.
The article link will be posted on the purchase transaction web page, and also emailed to you with your purchase confirmation.

Purchase This Article for Limited One-Time Distribution and Posting to Your Website :

Receive a formatted PDF reprint of this article, including any sub-articles, charts, tables and/or graphs related to this specific article, with rights for limited one-time redistribution and posting to your website: $750. Please allow 24-48 hours for delivery.

Purchase Options

Purchase this article for individual use $50 USDPurchase this article for limited one-time distribution and website posting $750 USD